Modulation of epidermal growth factor heterodimer activity

Abstract

Provided is a method for screening a plurality of compounds for an ability to bind to a heterodimer of EGFR and another ERBB family member. Also provided are compounds that bind to heterodimers of EGFR and another ERBB family member; and methods of using the identified compounds to suppress the growth of a tumor associated with EGFR heterodimer activity in a subject.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60 / 545,185, filed Feb. 17, 2004, the contents of which is herein incorporated by reference in its entirety.GRANT STATEMENT[0002]This work was supported by grants CA092479, CA084239, and HD039896 from the National Institutes of Health. Thus, the United States government has certain rights in the presently disclosed subject matter.TECHNICAL FIELD[0003]The presently disclosed subject matter relates generally to the modulation of the activity of a heterodimer of an epidermal growth factor receptor (EGFR) with other members of the ERBB family in the regulation of cellular proliferation, differentiation, and survival. More particularly, the presently disclosed subject matter relates to the modulation of the activity of EGFR / ERBB2, EGFR / ERBB3, and / or EGFR / ERBB4 heterodimers in the regulation of cellular proliferation, differentiation, and survival.BACKGROUND ART[...

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Benefits of technology

[0014]The presently disclosed subject matter also provides a compound identified by the disclosed methods. Such compounds can be employed for treating any disorder associated with undesirable EGFR heterodimer activity, for example, a tumor associated with EGFR heterodimer activity. Thus, the presently disclosed subject matter also provides a method for suppressing the growth of a tumor associated with EGFR heterodimer activity in a subject. In some embodiments, the method comprises administering to the subject bearing the tumor associated with EGFR heterodimer activity an effective amount of a compound identified by the disclosed methods, whereby growth of the tumor is suppressed. In some embodiments, the compound comprises an antibody or antibody fragment. In some embodiments, the antibody or antibody fragment is a single chain fragment variable (scFv) antibody or an Fab antibody. In some embodiments, the tumor is selected from the group consisting of benign intracranial meningiomas, arteriovenous malformation, angioma, macular degeneration, melanoma, adenocarcinoma, malignant glioma, prostatic carcinoma, kidney carcinoma, bladder carcinoma, pancreatic carcinoma, thyroid carcinoma, lung carcinoma, colon carcinoma, rectal carcinoma, brain carcinoma, liver carcinoma, breast carcinoma, ovary carcinoma, solid tumors, solid tumor metastases, angiofibromas, retrolental fibroplasia, hemangiomas, Karposi's sarcoma, head and neck carcinomas, and combinations thereof.

[0015]The present method can be employed to suppress the growth of a tumor in any organism. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.

[0016]The presently disclosed subject matter also provides a method for identifying an antibody that specifically binds to an EGFR heterodimer. In some embodiments, the method comprises (a) isolating a membrane fraction of a cell, wherein the membrane fraction of the cell comprises EGFR and at least one of ERBB2, ERBB3, and ERBB4; (b) immunizing a mammalian subject with the membrane fraction; and (c) purifying an antibody from the antisera that specifically binds to an EGFR heterodimer. In some embodiments, (i) the cell is a mammalian cell that does not normally express any member of the ERBB family; and (ii) the mammalian cell has been transformed with one or more expre...

Problems solved by technology

However, inappropriate expression and / or activity of the ERBB receptors has been associated with various tumors, including tumors of the breast, colon, lung, ovary, and head and neck, and also in glioma (Rasheed et al., 1999; Wong et al., 1992; Moscatello et al., 1995).

Each of these antibodies is believed to modulate receptor activity by blocking ligand binding and / or enhancing endocytosis of the receptor, thus limiting its availability to become activated by ligand binding.

However, they are likely to be non-specific for EGFR, with significant activity on other tyrosine kinases.

Despite these advances, current methods for modulating EGFR heterodimer activity are hindered by their reliance on modulators that also modulate the activity of homodimers of the ERBB family and / or other tyrosine kinases.

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